Under the accelerated approval, ALK-positive patients who are no longer responding to or cannot tolerate the ALK-targeted drug crizotinib (Xalkori®) may be treated with brigatinib. The approval makes brigatinib the fourth ALK-targeted drug to be approved by FDA and the third for use after treatment with crizotinib.

Up to 7% of patients with NSCLC have tumors with ALK gene alterations known as translocations. In these tumors, a piece of the ALK gene has fused to a piece of another gene, resulting in aberrant activity of the resulting ALK fusion protein. These ALK alterations typically occur in NSCLC tumors in people who have never smoked or were light smokers.

Currently, patients with metastatic ALK-positive NSCLC receive crizotinib as their initial, or first-line, treatment. Two other drugs that target ALK, ceritinib (Zykadia®) and alectinib (Alecensa®), are approved for use in patients whose tumors have stopped responding to crizotinib.

“Now we have an additional second choice,” said Wallace Akerley, M.D., of the Huntsman Cancer Institute at the University of Utah. “It gives us more options, but we do not yet have a way to decide which of the drugs available to us should [ideally] be given first, second, or third.”

The approval of brigatinib was based on results of a phase 2 clinical trial known as the ALTA trial, which showed shrinkage of tumors in roughly half of all study participants receiving either of two daily doses of brigatinib. The median duration of this tumor response was approximately 14 months.

Clinical Trial Shows Tumor Shrinkage

In the ALTA trial, 222 patients with NSCLC whose tumors had progressed while receiving crizotinib were randomly assigned to treatment with one of two doses of brigatinib (90 or 180 milligrams daily). The trial was designed to assess the drug’s effectiveness, as measured by the overall response rate—the percentage of patients whose cancer shrinks after treatment.

Preliminary results published May 5 in the Journal of Clinical Oncology (JCO) suggest that the median progression-free survival is somewhat longer at the higher dose.

In patients with tumors that had spread to the brain—a common and serious occurrence, especially in ALK-positive NSCLC—42% of those on the lower dose of brigatinib and 67% of those on the higher dose had shrinkage of brain metastases.

Common side effects—that is, those occurring in at least 25% of patients taking brigatinib—were nausea, diarrhea, fatigue, cough, and headache. The most common serious side effects were pneumonia and, in 3% to 6% of patients, a rare, early-onset lung condition that caused transient breathing problems within the first week of therapy at 90 milligrams (mg).

Brigatinib has a unique dosing schedule, Dr. Akerley noted. For the higher dose, the FDA prescribing information calls for starting all patients on 90 mg per day for 7 days and increasing to 180 mg per day if the drug is tolerated, which is thought to improve the tolerability of the higher dose.

Additional Studies Needed

Accelerated approvals, such as the one for brigatinib, are designed to speed the availability of drugs that treat serious conditions and fill an unmet medical need. These approvals are based on a surrogate endpoint, such as tumor shrinkage, that is believed to predict a clinical benefit.

Under an accelerated approval, FDA requires the drug company to conduct additional studies to confirm the anticipated clinical benefit, such as improved overall survival or improved quality of life. If the confirmatory trial shows a clinical benefit, FDA then grants traditional approval for the drug. If the confirmatory trial fails, the drug could be removed from the market.

In a news release, the manufacturer of brigatinib, Takeda, said that the phase 2 ALTA trial is still in progress and will assess overall survival, progression-free survival, and other secondary outcomes when more data are available.

Brigatinib is also being studied in a phase 3 clinical trial to compare its efficacy and safety with those of crizotinib as a first-line treatment in patients with ALK-positive, metastatic NSCLC, Takeda reported.

Brigatinib, crizotinib, and other ALK-targeted drugs work in part by blocking the activity of the ALK protein, ultimately inhibiting the growth of tumor cells whose growth is fueled by overly active ALK.

But patients typically develop resistance to these drugs when tumor cells develop new gene alterations, or secondary mutations, in the ALK gene that render the protein insensitive to the inhibitor.

Laboratory studies suggest that brigatinib can overcome a broader range of the resistance mechanisms that result from secondary mutations in the ALK gene compared with crizotinib, ceritinib, or alectinib, Dr. Akerley said. But it remains to be seen whether results “that have been seen in the Petri dish will translate to real outcomes for real patients,” he added.

Consistent with the laboratory findings, the trial leaders wrote in JCO, the PFS seen at the higher dose of brigatinib is the longest reported of any next-generation ALK inhibitor after treatment with crizotinib.

It will be important to compare the effectiveness of brigatinib with other drugs that target ALK, and determine the order to use the drugs in each patient, Dr. Akerley said. In the not-too-distant future, he continued, “we may biopsy the cancer a second time to look for new gene mutations, and then have the results tell us which drug should be used as second-line therapy.”

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